Transcriptomic characterization of early-onset colorectal cancer
Open Access
- Author:
- Marx, Olivia
- Graduate Program:
- Biomedical Sciences
- Degree:
- Doctor of Philosophy
- Document Type:
- Dissertation
- Date of Defense:
- July 25, 2024
- Committee Members:
- Lisa Shantz, Program Head/Chair
Prashant Nighot, Outside Unit Member
Gregory Yochum, Chair & Dissertation Advisor
Ryan Hobbs, Outside Field Member
Iryna Pinchuk, Major Field Member - Keywords:
- early-onset
colorectal cancer
transcriptomics
cancer - Abstract:
- Early-onset colorectal cancer (EOCRC), or those that occur in individuals before the age of 50, has been rising in global prevalence and incidence over the past several decades. Environmental influences, including generational lifestyle changes and rising obesity, contribute to these increased rates. Pathological and molecular characterizations show that EOCRC has a distinct presentation compared with later-onset colorectal cancer (LOCRC), or those that occur after the age of 50. While mutational differences between EOCRC and LOCRC have been identified, the functional differences caused by these mutations remain understudied. In this dissertation, we used transcriptome analysis to profile 21 EOCRC patients. We first characterized the deregulation of cancer hallmark genes in EOCRC using Gene Set Enrichment Analysis (GSEA). We identified strong deregulation of the oncogenic transcription factor MYC and its downstream targets and further found that MYC target expression could cluster patients into two groups. We identified MYC/PVT1 locus copy number gain in 35% of EOCRC patients, supporting it as a potential mechanism of MYC deregulation in EOCRC. We then compared the EOCRCs to a cohort of LOCRC patients matched for demographic and clinical characteristics and identified a gene signature unique to EOCRC. We found that this signature was a significant prognostic indicator for CRC. We then performed cell type deconvolution, and splicing analysis, and predicted alternatively spliced transcripts that could produce cancer neoantigens in EOCRC. This work implicated MYC in EOCRC and elucidated novel gene targets and splicing events uniquely deregulated in EOCRC. These findings may be used in the future as biomarkers or therapeutic targets for the growing population of EOCRC patients.